The synthetic triterpenoid bardoxolone methyl, also known as CDDO-Me and as “RTA 402,” has shown potent anti-inflammatory and anti-tumor properties in preclinical studies and in human clinical trials. In particular, bardoxolone methyl has shown significant anticancer activity in patients with advanced cancer, and has shown the ability to improve measures of kidney function, insulin resistance, glycemic control, and systemic cardiovascular disease in patients suffering from chronic kidney disease as a result of Type 2 diabetes.
In these studies bardoxolone methyl was administered orally in a crystalline form (“Form A”), once daily, at a variety of doses. In addition to the significant clinical efficacy noted in these studies, Form A bardoxolone methyl showed an excellent tolerability profile with very few drug-related side effects noted.
Pharmacokinetic data from these studies indicated, however, that Form A bardoxolone methyl has relatively low oral bioavailability. Fortunately, a non-crystalline form of bardoxolone methyl (“Form B”) also has been identified, which shows markedly superior oral bioavailability compared to Form A.
It is well understood that improved oral bioavailability is a desirable feature of a drug formulation, since it reduces the per-dose cost of active material and is consistent with the general medical principle of administering the lowest amount of a drug that is known to produce the desired effect. Conversely, low aqueous solubility resulting in poor oral bioavailability of potential drug candidates has been recognized as a significant challenge facing the pharmaceutical industry.
In fact, an estimated 25-30% of compounds in early development have poor bioavailability due to low solubility. The United States Food and Drug Administration has adopted a biopharmaceutics classification system (BCS) that classifies drugs intended for oral dosage according to solubility and membrane permeability. Drugs that are poorly soluble yet highly membrane permeable make up a substantial portion of drug candidates and are referred to as BCS class 2 drugs. For this class of drugs intended for oral dosage, improvements in effective bioavailability can occasionally be addressed by altering the solubility profile of the drug substance, either alone or via the use of functional excipients in an appropriate pharmaceutical composition.
Several techniques have evolved to improve the solubility of certain drug candidates that have the potential to be safe and effective. One such technique that has been explored is to formulate the drug using an amorphous form of the drug substance, either alone or in a polymer matrix. While improvements in aqueous solubility of amorphous forms over that of the corresponding crystalline forms of the drug substance have been documented, such systems are inherently unstable and may return to their thermodynamically more stable crystalline state. As a result, considerable research and experimentation often is conducted to define formulation systems that can yield formulations with acceptable shelf-life.
Because dissolution rates and solubility in physiological media are typically higher in the upper gastrointestinal system, formulations containing amorphous drug substances, if they can be developed, often behave differently in vivo, relative to those formulations containing the corresponding drug in a crystalline form. Formulations containing amorphous drug substances have been reported to produce bioavailability enhancements and have area-under-curve (AUC) values several-fold higher than formulations containing the corresponding crystalline form of the drug substance on an equivalent dose basis. While it is not unusual for amorphous forms of drugs, once absorbed into general circulation, to exhibit similar metabolism, distribution, and excretion profiles, the time to maximal plasma concentration (Tmax) and the maximal concentration observed (Cmax) often are altered markedly in formulations containing amorphous drugs compared to their crystalline counterparts.
If a drug exhibits toxicity or is associated with an increased frequency of adverse events above a certain limiting plasma concentration, then maintaining therapeutic plasma levels safely below such a limiting level may be of paramount importance. Thus, even if a drug has a broad therapeutic window and is otherwise safe and effective, the control of Cmax or Tmax profiles may be important if the drug is to be administered chronically. More generally, if a particular plasma concentration profile is associated with a desirable profile of safety and efficacy, it is useful for alternative formulations containing the same active ingredient to produce a comparable plasma concentration profile.